Older adults are defined as those greater than or equal to 65 years of age, and demographics show that they are the fastest growing segment of the population. Epidemiological data indicate that the prevalence of epilepsy in the elderly is higher than in any other age group. As the population continues to grow and age, the number of older adults with epilepsy continues to increase. Recently, scholars have paid more and more attention and research on geriatric epilepsy, but there is still a lack of research on geriatric epilepsy. The complexity and diversity of the etiology of geriatric epilepsy patients, and most of them are secondary, such as: cerebrovascular diseases, neurodegenerative diseases, traumatic brain injury, and brain tumors can all have secondary epilepsy. The special characteristics of elderly patients make the diagnosis of epilepsy in the elderly more difficult than in children and young adults.
Older adults face additional and more complex issues, including medical complexities such as correct diagnosis, selection of the most appropriate medication, the presence of some co-morbidities, and other social factors such as emotional stability and financial burden. The selection of medications for the treatment of geriatric epilepsy requires comprehensive consideration of multiple factors, the presence of co-morbidities requires consideration of drug interactions, and the use of antiepileptic drugs needs to reduce the number of seizures in geriatric patients while also considering the impact on cognition, sleep, mental behavior, and other functions of geriatric patients, thus improving the quality of life of geriatric patients with epilepsy. In this paper, we review the progress related to the etiology and treatment of geriatric epilepsy.
I. Etiology of geriatric epilepsy
The majority of geriatric epilepsy is secondary, and in some cases, no clear cause or cryptogenic origin can be found, while idiopathic epilepsy associated with genetic factors is rare. The most common secondary cause is stroke, which accounts for 30-40% of cases. In addition, brain tumors, head trauma, Alzheimer’s disease, and central nervous system infections are more common causes.
1. Cerebrovascular disease: Stroke and other cerebrovascular diseases are the most important risk factors for epilepsy in the elderly, and the risk of seizures will increase 20-fold in the year following a stroke. In most cases, epilepsy occurs within three months to one year after a stroke. Seizures occurred more frequently in hemorrhagic strokes than in ischemic strokes, 25% and 9.5%, respectively. Seizures are associated with a variety of factors, such as cortical lesions, hemorrhagic, large, diverse, and concomitant acute epileptiform seizures of stroke in patients prone to complications of epilepsy.
2, neurodegenerative diseases: 10-20% of elderly patients with epilepsy suffer from dementia or neurodegenerative diseases. Seizures can occur during any period of degenerative disease, and are especially likely to occur in advanced stages. A retrospective study of 453 patients with milder Alzheimer’s disease found that through 5 years of follow-up, 2% of patients had non-stimulated seizures and were 8 times more likely to have seizures than the general population, with younger patients at greater risk.
3. Trauma: The cause of 20% of epilepsy in the elderly is head trauma, the most common cause of intractable epilepsy. A study in off post-traumatic epilepsy showed that the odds of epilepsy were highest within one year after trauma, and the risk of epilepsy onset remained higher ten or ten years after trauma than in people with no history of trauma. Brain contusion combined with subdural hematoma, skull fracture, loss of consciousness, memory loss for more than one day, and age greater than or equal to 65 years are all risk factors for complications of epilepsy.
4. Tumors: About 10-30% of seizures are related to tumors, especially gliomas, meningiomas, and brain metastases. Seizures are more common in patients with primary brain tumors than secondary tumors, and the incidence is higher in patients with hypofractionated tumors than in those with highly differentiated tumors.
5. Central nervous system infection: Elderly people, especially those with underlying diseases, have lower immunity and are prone to central nervous system infectious diseases, such as tuberculosis, syphilis, HIV, parasites, etc. Secondary epilepsy after CNS infection is more common in developing countries than in developed countries.
6. Drugs and toxins: Due to the presence of co-morbidities in the elderly, the drugs used have the potential to have epileptogenic effects. For example, antipsychotics, antidepressants, antibiotics, theophylline, levodopa, thiazide diuretics, bupropion, clomipramine, selective serotonin uptake inhibitors such as fluoxetine and phenothiazines, in addition to alcohol withdrawal and CO intoxication can induce seizures.
In addition, electrolyte disorders, febrile diseases, hypoglycemia or hyperglycemia and metabolic diseases such as hypothyroidism can also induce seizures, but these conditions are easily detected by laboratory tests and physical examinations, and often do not require long-term treatment with antiepileptic drugs.
Second, the treatment of epilepsy in the elderly
The goal of antiepileptic drug therapy is to improve quality of life by providing complete seizure control with no side effects. The key to treatment of geriatric epilepsy is to identify the cause. Generally, a single seizure does not require antiepileptic treatment, but recurrent seizures require prompt treatment. Secondary epilepsy is treated primarily for the primary cause, and most seizures no longer occur after the cause is removed. Seizures of unknown etiology, especially in patients with a prior history of stroke, require prompt administration of antiepileptic drugs because the risk of recurrence is high and recurrence can be fatal.
1. Pharmacology and interactions of antiepileptic drugs in the elderly
AEDS ranks fifth among all drug classifications in terms of drug side effects in the elderly. The drug concentration at the site of action determines the expected effect and side effects, and the free drug concentration in the serum is directly related to the drug concentration at the site of action and provides the optimal drug response. To select the appropriate antiepileptic drug requires consideration of multiple factors, such as decreased organ function in the elderly, increased drug side effects, the use of other drugs that may interact with AEDS, the impact of cognitive function in the elderly, and the financial limitations of the elderly patient.
There are very few studies on geriatric epilepsy, and combination therapy with multiple drugs is the basic rule of thumb for medication in the elderly, especially for seizures caused by cerebrovascular disease. In a study of elderly patients with epilepsy, one quarter of them were taking 15 or more drugs concurrently (average of 7 drugs), and the more drugs taken concurrently, the worse the outcome and the greater the risk of drug interactions.
Enzyme induction is a prominent problem, for example phenobarbital, paracetamol (metabolized to phenobarbital), phenytoin and carbamazepine increase the metabolism of many commonly used drugs, including warfarin, cytotoxins, theophyllines, statins, antiarrhythmics, antihypertensives, macrolide antibiotics, corticosteroids and other immunosuppressive drugs.
Some commonly used drugs such as propoxyphene, erythromycin, cimetidine, diltiazem, fluoxetine, paroxetine, verapamil, valproate, and alcohol inhibit the metabolism of AEDS through the P450 enzyme system. Calcium-containing antacids and aluminum thioglycollate can reduce the absorption of phenytoin, and oral antineoplastic drugs significantly reduce the absorption of phenytoin, valproate, and carbamazepine due to damage to cells in the gastrointestinal tract.
In addition, antineoplastic drugs given intravenously also decrease the concentration of phenytoin. The interaction between antipsychotic drugs and AEDS is complex. Hepatic metabolism of some antipsychotics such as haloperidol is increased by the use of carbamazepine, which reduces the effect of antipsychotics. Antipsychotics, especially chlorpromazine, promethazine, and endorphin, can lower the seizure threshold, and the risk of seizures is proportional to the total amount of antipsychotics used.
2. The influence of concomitant diseases on the selection of antiepileptic drugs in elderly patients
The selection of AEDS in elderly patients requires a combination of various factors. Currently, newer antiepileptic drugs such as oxcarbazepine, lamotrigine, Tolteraz, and levetiracetam are mostly used. The biggest advantage of newer antiepileptic drugs compared to traditional antiepileptic drugs is that they interfere less with each other, but are more expensive. For elderly patients with epilepsy only, especially if they have financial problems, traditional antiepileptic drugs can be preferred, but attention must be paid to their side effects, for example, valproic acid is not preferred if there is tremor, carbamazepine is not preferred if there is sodium ion disorder, phenytoin is not preferred if there is ataxia, and gabapentin is optional if there is combined neuralgia.
For elderly patients with multiple diseases, newer antiepileptic agents need to be preferred because of the need for concurrent use of other drugs and the need to consider fewer drug interactions and safety. In addition, it is necessary to pay attention to the clearance rate and free blood drug concentration of AEDS drugs and to closely observe their adverse effects.
3. Effects of drug therapy on elderly patients with epilepsy.
(1) Cognitive decompensation
Many elderly patients with epilepsy have cognitive impairment. Seizures and antiepileptic drugs may lead to cognitive decompensation, and the impairment of cognitive function is persistent, in which memory impairment has an impact on many aspects of life. The conventional AEDS phenobarbital and paromidone have an effect on cognitive function, especially when used in high doses. Patients with focal epilepsy are more susceptible, but milder deficits in neurocognitive function can also be seen in patients with generalized epilepsy. Patients with temporal lobe epilepsy are more likely to have memory problems than other focal epilepsies. Medial temporal lobe sclerosis is often a potential cause of memory loss.
(2) Mental-behavioral abnormalities
It is known that people with epilepsy are more likely to have abnormal psychiatric behavior than the general population, and one study reported that the risk of abnormal psychiatric behavior in people with epilepsy is 2-3 times higher than in normal people. Factors hypothesized to be associated with the occurrence of psychiatric behavioral abnormalities in patients with epilepsy may include: intelligence, genetics, clinical features associated with seizures, and EEG abnormalities.
However, the effect of AEDS on psychiatric symptoms remains controversial, with some scholars insisting that the appearance of psychobehavioral abnormalities is caused by the use of specific AEDS, but others pointing out that psychobehavioral abnormalities are still present or recur in about 20-40% of patients even after discontinuation of AEDS suspected of affecting psychiatric behavior. A regression analysis has shown that zonisamide may trigger a variety of psychiatric symptoms, including depression, anxiety, irritability, and psychosis.
An animal study showed that zonisamide was associated with increased extracellular dopamine levels in the striatum and hippocampus of rats, and this finding is consistent with several other studies demonstrating the effectiveness of zonisamide in the treatment of Parkinson’s disease. Thus, the effect of zonisamide on dopamine levels may be related to the development of psychosis, although it is unclear whether zonisamide monotherapy leads to psychiatric side effects.
The current study suggests that phenytoin is associated with the development of psychosis and, in fact, may cause schizophrenia-like psychosis when phenytoin serum levels are higher than 35 mg/l. However, psychotic side effects occur in epileptic patients treated with phenytoin even after the toxicity of phenytoin has been carefully excluded. Recent studies have not included topiramate as a factor affecting psychiatric behavior; however, rating alone suggests that topiramate has the highest probability of causing psychiatric abnormalities among the new AEDS, with the exception of zonisamide.
The role of levetiracetam and psychiatric behavior remains controversial. The current study shows that gabapentin and lamotrigine are negatively associated with abnormal psychiatric behavior, which is consistent with previous studies, and also demonstrates that the use of both drugs is beneficial for psychiatric functioning. In conclusion, there are effects of AEDS on psychiatric behavior, especially when used with caution in psychosis-prone older adults.
(3) Sleep disorders
The older the person, the greater the likelihood of sleep disorders, and sleep disorders are a particularly prominent problem for older patients with epilepsy. The idea that sleep disorders are one of the co-morbidities of epilepsy has been increasingly recognized by scholars. Sleep disorders such as insomnia, obstructive sleep apnea syndrome, and excessive daytime sleepiness increase the frequency of seizures and decrease the quality of life for people with epilepsy. Poor sleep quality may also swiftly lead to cognitive decline; therefore, improving sleep quality can be helpful in controlling seizures as well as improving cognitive function.
(4) Osteoporosis and fractures
Osteoporosis and fractures are common in older adults, and the risk is higher in older patients with epilepsy. The occurrence of epilepsy increases the risk of falls and fractures by a factor of 2 to 6. The enzyme induction of antiepileptic drugs accelerates the catabolism of vitamin D, which reduces calcium absorption, causes and secondary hyperparathyroidism, and increases bone loss. Numerous prospective studies have shown that the combined use of phenytoin sodium and gabapentin in men and women will reduce bone mineral density. In addition, lack of exercise, inadequate nutrition, emotional instability and dysregulation of neurological homeostasis, and protective reflexes may all play a role in older patients.
In summary, the prevalence of geriatric epilepsy continues to grow as the population ages. The elderly are not a simple population with a large age span, and the characteristics of different categories of elderly patients with epilepsy need to be further investigated in depth. This is because the complexity of the clinical seizure characteristics makes the correct diagnosis of epilepsy in the elderly more difficult compared to younger people. Obtaining a reliable description of the seizure event and an accurate assessment to guide the appropriate tests is essential to make the correct diagnosis.
Altered pharmacokinetics and pharmacodynamics, the presence of co-morbidities, drug interactions, and concomitant dysfunction in the elderly make the selection and use of antiepileptic drugs more complex. There is a paucity of high-level clinical studies on the etiology, clinical features, and selection of therapeutic agents for the treatment of geriatric epilepsy, and further research is needed. The prognosis of elderly patients with epilepsy can only be improved by making a correct diagnosis, choosing a reasonable and effective treatment plan, and paying attention to the psychological effects of the elderly.